Psychopharmacology (1996) 127:225-230 © Springer-Verlag 1996

David C. Jewett • Henry I. Mosberg James H. Woods Discriminative stimulus effects of a centrally administered, delta- (o-Pen2-o-PenS-) in pigeons

Received: 26 April 1995 / Final version: 9 December 1995

Abstract The present study assessed the discriminative Introduction stimulus effects of the delta-opioid [D-Pen2-D- PenS]enkephalin (DPDPE) in pigeons. Food-restricted produce their effects through three major types of pigeons were trained to discriminate between ICV injec- opioid receptors, ran, kappa, and delta. Drug discrimina- tions of 100 gg [D-Pen2-D-PenS]enkephalin (DPDPE) and tion studies using receptor-selective and antago- saline in a two-key operant procedure; acquisition of dis- nists have made important contributions in characterizing criminative control was rapid (14-28 daily sessions). [D- these receptors. Distinct discriminative stimulus effects of Ser2, Leu 5, Thr6]enkephalin (DSLET) and [D-Ala2]del - mu- and some kappa-opioid agonists have been character- torphin II, selective for delta-opioid receptors, ized in pigeons. For example, produced dis- produced discriminative stimulus effects similar to criminative stimulus effects similar to those of another DPDPE, and were approximately equipotent to DPDPE. highly selective kappa agonist, U50,488, but neither pro- The non-peptidic, delta-opioid agonist BW373U86 duced -like discriminative stimulus effects (Pick- (0.032-100 mg/kg, IM) partially generalized to DPDPE. er and Dykstra 1987; although some kappa-opioid ago- The kappa-opioid agonist U69,593 (0.01-1 mg/kg, IM), nists do produce morphine-like discriminative effects, see and the mu-opioid agonists, DAMGO (0.1-3.2 gg, ICV) Herling et al. 1980). A larger dose of is required and morphine (1-10 mg/kg, IM), did not produce dis- to reduce the potency of U50,488 as a discriminative stim- criminative stimulus effects similar to DPDPE, up to ulus than is required to reduce morphine's potency (Picker doses that markedly decreased response rates. Nattrin- and Dykstra 1987). Discriminative stimulus effects of del- dole (0.1 mg/kg, IM), an antagonist selective for delta- ta- agonists, however, have not been stud- opioid receptors, produced approximately a 30-fold re- ied extensively. One possible reason for the paucity of duction in the potency of DPDPE. DPDPE's discrimina- drug discrimination information on delta-opioid agonists tive stimulus effect in pigeons appears to be mediated is that most agonists at delta-opioid receptors are peptides, through a delta-opioid receptor; this effect may provide a have difficulty crossing the blood-brain barrier, and proba- procedure for assessing delta-opioid receptor function in bly need to be administered centrally. vivo. To date, only one study has demonstrated discrimina- tive stimulus effects mediated through a delta-opioid re- Key words [D-Pen2-D-PenS]enkephalin (DPDPE) • ceptor (Comer et al. 1993). The discriminative stimulus [D-Ser 2, Leu 5, Thr6]enkephalin (DSLET) • effects of IM BW373U86 were antagonized by small [D-Ala2] II- BW373U86 • doses of , which is more potent in antagoniz- Drug discrimination • Pigeons • Delta opioids • ing delta-opioid effects than mu- or kappa-opioid medi- Operant behavior ated effects. Interestingly, central administration of the prototypic delta-opioid receptor agonists DPDPE and DSLET did not produce a discriminative stimulus similar to that of BW373U86. Additionally, a portion of D. C. Jewett (~). J. H. Woods BW373U86's discriminative stimulus effects were Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, shared with mu-opioid agonists. Systemically adminis- Ann Arbor, MI 48109-0632, USA tered morphine, , and all produced H. I. Mosberg partial generalization to the BW373U86 discriminative Department of Medicinal Chemistry, stimulus, and BW373U86 partially generalized to mor- University of Michigan Medical School, phine in pigeons trained to discriminate 5.6 mg/kg mor- Ann Arbor, MI 48109-0632, USA phine from saline. 226

Few studies have established discriminative stimulus procedm'es and a Rezvin adapter (Karten and Hodos 1967). A 28 g effects based on centrally administered compounds (see, dummy cannula was inserted into the guide cannula except during ICV injections. The patency of the cannula was assessed by ICV however, Jewett et al. 1991, 1993). Some studies have injection of radioopaque dye (Conray: Mallinckrodt, St Louis, assessed the ability of proposed delta-opioid agonists Mo.) or by catalepsy induced by 17.2 gg 2-amino-5-phosphono- (e.g. D-Ala 2, D-LeuS-enkephalin; DADLE) to produce valerate (Koek et al. 1985; AP5; Sigma, St Louis, Mo.). discriminative stimulus effects similar to mu-opioid ago- nists. In rats, centrally administered DADLE produced discriminative stimulus effects similar to , but Procedures not ethylketocyclazocine (Shearman and Herz 1982). In Discrimination training rats trained to discriminate mol~hine from saline, ICV DADLE produced a morphine-like discriminative stimu- Pigeons were initially trained to peck a single (center) illuminated lus but ICV [D-Pen2-L-PenS]enkephalin (DPLPE), which key to obtain access to mixed grain by the method of successive approximations. Initially, one key-peck produced food access. has greater selectivity for delta-opioid receptors than This response requirement was gradually increased until 20 key- DADLE, did not (Ukai and Holtzman 1988). That pecks were required to produce access to mixed grain (FR 20; DPLPE did not produce its effects through mu- or kappa- Ferster and Skinner 1957). When responding was reliable (greater opioid receptors does not prove that DPLPE, and ago- than 1.5 responses/s), pigeons were implanted with cannulae in the right lateral ventricle. Following and a 1-week recovery nists more selective than DPLPE for delta-opioid recep- period, discrimination training began. tors, produce their effects through delta-opioid receptors. Pigeons were trained to discriminate between an ICV injection The goals of the present study were to establish a dis- of 100 gg DPDPE and an equal volume (10 gl) of saline. Daily crimination based on the central administration of training sessions consisted of one trial per day. The first three DPDPE, a peptide highly selective for delta opioid re- training sessions were preceded by an injection of saline, after which the pigeon was placed in the operant chamber for 10 min. ceptors (Mosberg et al. 1983). The ability of selective During this time, the chamber was dark, and responses had no pro- agonists for mu- (DAMGO, morphine), kappa- grammed consequences. At the end of the pretreatment time, the (U69,593) or delta- (BW373U86, DSLET, deltorphin II) left key was illuminated, and 20 responses on the key produced 5- opioid receptors and a non-opioid () to produce s access to mixed grain. The training session continued until 25 re- inforcers were earned or 30 rain, whichever occurred first. The discriminative stimulus effects similar to DPDPE was next three training trials were preceded by an injection of 100 gg also assessed. To demonstrate further the receptor selec- DPDPE, and following the 10-min pretreatment period, only the tivity of DPDPE's discriminative stimulus effects, exper- right key was illuminated. Pecks on this key produced access to iments were performed using naltrindole, an antagonist mixed grain under an FR 20. Following these six sessions, dis- crimination training began. These training sessions consisted of an selective for delta-opioid receptors. injection of either DPDPE (100 ~tg) or saline, the 10-min pretreat- ment period, and a 30-rain response period. Both response keys were illuminated during the response period. Responses on the in- Materials and methods jection-appropriate key (right following DPDPE; left following sa- line administration) were reinforced by 5-s access to mixed grain under an FR 20. Responses on the incorrect key had no pro- Subjects grammed consequences. Sessions preceded by DPDPE and saline Ten experimentally naive white Carneaux pigeons were used in alternated randomly with the restriction that no more than two the present studies. All pigeons were maintained at 80% of their consecutive sessions of DPDPE or saline administration occurred. free-feeding weight by mixed grain availability during experimen- Discriminative control was defined as 1) greater than 50% of tal sessions and Purina Pigeon Checkers received post-session in the responses prior to the first reinforcer delivery, and 2) greater the home cage. All subjects were housed individually with water than 90% of the responses for the total session, on the injection- and grit freely available. appropriate key. Additionally, response rates were required to be greater than one response/s. Before discrimination testing began, subjects were required to meet these criteria for eight consecutive Apparatus training sessions. Thereafter, tests were conducted whenever crite- ria were met for two consecutive sessions (a session preceded by Experimental sessions were conducted in operant chambers DPDPE, and a session preceded by saline administration). (36x28x33 cm high) equipped with three translucent response keys (2.4 cm diameter) that could be illuminated by 7-W red lights located behind each key. Food was presented via a hopper that piv- Discrimination testing oted into an opening located below the center response key. Oper- ant chambers were located in ventilated, sound-attenuating cubi- A single dosing procedure was used to assess the time course of cles. Experimental contingencies were arranged and data were re- DPDPE's (100 gg) discriminative stimulus effects in five pigeons. corded by MED-PC software (MED Associates, East Fairfield, The stimulus effects were evaluated 0, 5, I0, 20, 40, 80, t60, and Vt.) and an IBM PC computer, located in an adjacent room. 320 rain after a single injection of 100 gg DPDPE. At each time point, a response period was initiated during which pigeons ob- tained access to food by for pecking either response key under an Surgery FR 20. The response period continued for 5 rain, or until ten rein- forcers were delivered. The details of the surgical procedure have been described previ- Tests assessing the ability of DPDPE and other drugs to either ously (France et al. 1985). Briefly, pigeons were anaesthetized produce discriminative stimulus effects similar to those of 100 gg with 2.5-2.75 ml/kg Chloropent (chloral hydrate and pentobarbit- DPDPE, or to antagonize the discriminative stimulus effects of al: Fort Dodge Laboratories, Fort Dodge, Iowa) and 8 mg/kg ket- DPDPE involved the use of cumulative dosing procedures. The amine. A chronic, indwelling cannula (Plastic Products, Roanoke, testing procedure consisted of several trials composed of a 10-rain Va.) was implanted in the right lateral ventricle using stereotaxic time-out period, and a response period. During the response peri- 227

od, 20 responses on either key resulted in food presentation, and N too I 00 continued for 5 min, or until ten reinforcers were delivered. After "co N each trial, additional drug was administered (in 1/2 or 1/4 log unit ~- g 80 80 "U UJ increments) and a new trial began. This sequence continued until & 0~ 713"13 responding was reduced to less than 0.3 responses/s or until the ~- = 60 80~ T solubility limit of the test drug precluded additional testing. Two ~: g- groups of pigeons (n=5 per group) were used in the present stud- ~_ ~ 40 48 ~ ies. In one group, tests were conducted with DPDPE, DSLET, and ITL deltorphin II (all administered ICV). These pigeons also received c~ 2o 20 ~° IM injections of morphine, U69,593 and BW373U86 prior to test sessions. Another group of pigeons were tested with increasing o 0 o doses of DPDPE (ICV), DAMGO (ICV), and cocaine (IM). Addi- S 1 I0 t O0 0 t 0 4-0 160 tionally, these pigeons received naltrindole (IM) 15 rain prior to Dose (/zg, icy.) Time (rain) increasing doses of DPDPE. Fig. 1 A DPDPE dose-effect curve in pigeons trained to discrimi- nate 100 gg DPDPE from saline. Response rates were not affected Data analysis by DPDPE administration (data not shown). B Time course of the discriminative stimulus effects of 100 gg DPDPE. Points are Results are presented as the mean (_+SEM) percentage of respons- means (--+-SEM),n=5 es on the DPDPE-appropriate key as a function of dose. Com- pounds were considered to have partially generalized to DPDPE if they resulted in greater than 10%, but less than 90% DPDPE-ap- propriate responding. Compounds completely generalized to sponding (Fig. 1, panel A). Following 32 btg DPDPE, four DPDPE if they resulted in at least 90% responding on the DPDPE- of five pigeons responded the DPDPE-appropriate key, and appropriate key. Response rates are expressed as means (+SEM) complete generalization occurred after 100 btg DPDPE. and are plotted as a function of dose administered. EDs0s were cal- Subjects responded on the saline-appropriate key following culated using procedure #8 in the Pharmacological Calculation System of Tallarida and Murray (i987). This procedure does not administration of ICV saline (10 btl, ICV). exclude data points less than 20% or greater than 80% effect lev- The training dose of DPDPE (100 gg) had a rapid onset els. Reductions in DPDPE's potency by naltrindole are expressed and long duration of action (Fig. 1, panel B). Four of five as a dose ratio (DR) between the EDs0 of DPDPE in the presence pigeons responded exclusively on the DPDPE-appropriate of 0.1 mg/kg naltrindole and the EDs0 of DPDPE alone. EDs0 val- ues for DPDPE and DPDPE in combination with naltrindole were key immediately after DPDPE administration. All subjects considered to be significantly different if the 95% confidence lim- responded on the DPDPE-appropriate key 5 rain after ad- its did not overlap. In vivo apparent pKB values were determined ministration, and responded on this key up to 80 rain after for naltrindole in combination with DPDPE using the equation DPDPE administration. After 160 rain, only 25% of the re- pKB=-log [B/(DR-1)] (Negus et al. 1993). The variable "B" sponses were emitted on the DPDPE-appropriate key. No equals the dose of naltrindole in mot/kg. DPDPE-appropriate responding was observed 320 rain af- ter its administration. Response rates were not affected by Drugs this dose of DPDPE (data not shown). Subjects responded on the saline-appropriate key following administration of [D-Pen2, D-PenS]enkephalin, [D-Ser2, Leu 5, Thr6]enkephalin (DSLET), [D-Ala2]deltorphin II (all synthesized by H. I. Mosberg ICV saline (10 gl, ICV) at all time points tested. and colleagues), U69,593 (Upjohn Co., Kalamazoo, Mich.), mor- phine sulfate (Mallinckrodt, St Louis, Mo.), [D-AIa2, NMePhe 4- Met(O)5-(ol)]enkephalin (DAMGO) (Sigma, St Louis, Mo.), naltr- Discrimination tests and cocaine (National Institute on Drug Abuse, Rockville, Md.) were dissolved in sterile water or saline (0.9%). DSLET and deltorphin II, administered ICV, caused a dose- dependent increase in DPDPE-appropriate responding (Fig. 2, top panel). DSLET was 10- to 30-fold more potent Results than deltorphin II and DPDPE in tt~ee of the pigeons test- ed, but DPDPE, DSLET, and deltorphin II resulted in great- DPDPE acquisition and duration er than 90% DPDPE-appropriate responding in all pigeons of discriminative effects following 100 gg. Response rates were not affected by any doses of DSLET and deltorphin II tested. No DPDPE-ap- Pigeons rapidly learned to discriminate DPDPE from sa- propriate responding was observed following ICV injec- line. Stimulus control was attained in an average of 22 dai- tions of DAMGO, although doses of 1 btg or greater mark- ly sessions (range 1428) from the beginning of the edly reduced responding (Fig. 2, bottom panel). "choice" procedure to the session immediately preceding The ability of mu- and kappa-opioids and cocaine to the eight consecutive sessions demonstrating stimulus con- produce a discriminative stimulus similar to DPDPE was trol. During these eight sessions, every pigeon averaged also assessed. Intramuscularly administered morphine, greater than 92% injection-appropriate responding prior to U69,593, and cocaine did not produce discriminative the first reinforcer, and greater than 97% injection-appro- stimulus effects similar to those of DPDPE (Fig. 3) al- priate responding for the entire session. Response rates though these drugs markedly reduced responding. On the were unaffected following administration of 100 btg other hand, BW373U86, an agonist selective for delta- DPDPE (2.0+0.2 r/s) or saline (2.2+0.3 r/s). DPDPE pro- opioid receptors, produced 30-60% DPDPE-appropriate duced dose-dependent increases in DPDPE-appropriate re- responding over a wide dose range (0.1-32 mg/kg, IM). 228

100 100 ~/!~ • DPDPE + NTt (i.m.) "~ BO ~L "~- BO 4>0.01 mg/kg IzXO-1 mg/kg I o_¢n 60

? X+o LOI 0..40

o_ 20 ~cc: 20 CI 0 0 A 0.1 1 10 100 1 t0 100 IOO0 DPDPE (~g, icy.) "~"3 ~3

v ~2 o 2 r,,. c I o 8_ t~ Q) r~ 0 I I ~ I I rv" 0 0.1 1 10 100 1 10 100 1000 ,u,gi.c.v. DPDPE (/~g, icv.) Fig. 2 Dose-effect curves for ICV Deltorphin II (Delt. I1), DSLET Fig. 4 Effects of naltrindole (0.01 and 0.1 mg/kg) on the discrimi- and DAMGO in pigeons trained to discriminate DPDPE (100 gg) native stimulus and rate-decreasing effects of DPDPE. Top panel: from saline. Top panel: ordinate: percentage of DPDPE-appropri- percentage of DPDPE-appropriate responses. Bottom panel: re- ate responses. Abscissa: agonist of dose (log scale). Bottom panel: sponse rate (responses/s). Points are means (_+SEM), n=5 response rate expressed in responses/s as a function of dose. Points are means (+SEM), n=5 were unaffected following 1-100 gg DPDPE, but re-

e lOO sponding was suppressed following 320 gg. • U69,593 Pretreatment with naltrindole (0.01-0.1 mg/kg IM) •r- 8o ~f Morphine produced a dose-dependent shift in the discriminative l- 02 yCocaine ~m 60 stimulus effects of DPDPE (Fig. 4). Naltrindole '< o / ~# 40 (0.1 mg/kg, IM), produced approximately a 30-fold re- duction in the potency of DPDPE to produce its discrim- o_ 20 C3 inative stimulus and response rate decreasing effects. N 0 The apparent pK R value for naltrindole (0.1 mg/kg) 0.01 al 1 10 100 against DPDPE was 8.3.

v Discussion ~2 The goals of the present studies were to establish DPDPE as a discriminative stimulus and to determine o 13- the opioid receptor type mediating this effect. The pres- 0 ent studies demonstrate that DPDPE was discriminable, 0.01 0.1 1 10 100 and that its discriminative stimulus effects were mediat- mg/kg, i.m. ed through a delta-opioid receptor. Administration of the peptidic, delta-opioid agonists DSLET and deltorphin II Fig. 3 Dose-effect curves for IM morphine, U69,593, BW373U86 and cocaine in pigeons trained to discriminate ICV DPDPE resulted in DPDPE-appropriate behavior. DPDPE, (100 gg) from saline. Top panel: percentage of DPDPE-appropri- DSLET and deltorphin II were equipotent in producing ate responses. Bottom panel: response rate (responses/s). Points DPDPE-like discriminative stimulus effects in pigeons, are means (_+SEM), n=5 although DSLET was more potent in three of five pi- geons tested. In mice, DPDPE and deltorphin II both produced antinociceptive effects, assessed using the Naltrindole antagonism of DPDPE discriminative warm-water tail-withdrawal assay, and both were antago- stimulus effects nized by delta-receptor-selective antagonists (e.g., Jiang As shown in Fig. 4, administration of increasing doses of et al. 1990). In mice, deltorphin II was 3-fold more po- DPDPE produced dose-related increases in DPDPE-ap- tent than DPDPE in producing antinociceptive effects, propriate responding. Complete generalization (>90% and tolerance developed to deltorphin II and DPDPE, but DPDPE-appropriate responding) occurred after adminis- no cross-tolerance was found between them, suggesting tration of 32 gg DPDPE in these pigeons. Response rates that these effects were produced through different sub- 229 types of delta-opioid receptors (Mattia et al. 1991). In and response rate decreasing effects (D.C. Jewett, un- the present study, the finding that deltorphin II and published observations). The apparent pK B value for DSLET produced discriminative stimulus effects similar naltrindole with DPDPE (8.3) was similar to the appar- to DPDPE suggests that a similar receptor type mediates ent pA 2 value obtained by Comer et al. (1993) for naltr- this effect in pigeons. indole with BW373U86 in the pigeon (7.9_+0.5). Only one previous study has described the acquisition The discriminative stimulus effects of DPDPE were of discriminative stimulus effects mediated through del- acquired rapidly. Subjects learned to discriminate ta-opioid receptors in pigeons (Comer et al. 1993). Al- DPDPE from saline in 14-28 sessions. Few studies have though BW373U86's discriminative stimulus effects established discriminative stimulus effects using a cen- were antagonized by small doses of naltrindole, its stim- trally administered drug. In those instances, the training ulus effects, were partially mediated through mu-opioid drug's discriminative stimulus effects have been rapidly receptors. The mu-opioid agonists morphine, alfentanil, acquired (within 14 daily sessions; Jewett et al. 1991, and etonitazene produced some BW373U86-appropriate 1993). At present, it is unclear if discriminative stimulus responding. Also, BW373U86 produced some morphine- effects are acquired faster via central administration. appropriate responding. These results suggested that mu- Further research with a variety of compounds, especially opioid receptors are at least partially involved in the dis- those that can be established as discriminative stimuli by criminative stimulus effects of BW373U86. In pigeons systemic administration, would be useful to address this trained to discriminate DPDPE from saline, BW373U86 issue. produced some DPDPE-like discriminative stimulus ef- fects over a wide dose range. Taken together, these find- Acknowledgements This research was supported by USPHS ings are consistent with the notion that BW373U86's dis- Grants DA-07268, DA-05325 and DA-00254. The authors thank criminative stimulus effects are complised of both a del- Christian Raphatides for excellent technical assistance. Animals used in this research were maintained in accordance with the Uni- ta-opioid component and mu-opioid component. versity Committee on Use and Care of Animals, University of Discrimination tests did not provide evidence for oth- Michigan, and guidelines of the Committee on Care and Use of er opioid receptor mechanisms or cocaine-related mecha- Laboratory Animals Resources, National Research Council [De- nisms modulating the discriminative stimulus effects of partment of Health, Education and Welfare, Publication No. (NIH) 85-23, revised 1985]. DPDPE. Mu-opioid agonists DAMGO (ICV) and mor- phine (IM) failed to produce a discriminative stimulus effect similar to DPDPE at active doses. The kappa-opio- id agonist U69,593 and cocaine (IM) did not produce References DPDPE-like discriminative stimulus effects. In rats, Comer SD, McNutt RW, Chang K-J, De Costa BR, Mosberg HI, some studies have revealed interactions between delta- Woods JH (1993) Discriminative stimulus effects of opioid receptor mechanisms and cocaine related mecha- BW373U86: a nonpeptide ligand with selectivity for delta opi- nisms. For example, in rats trained to discriminate co- oid receptors. J Pharmacol Exp Ther 267:866-874 caine from saline, DPLPE produced discriminative stim- Ferster CB, Skinner BF (1957) Schedules of reinforcement. Ap- pleton Century Crofts, New York ulus effects similar to those of cocaine (Ukai et al. 1993). France CP, Adams JU, Woods JH (1985) Intracerebroventricular In addition, naltrindole and , antagonists selec- drug administration in pigeons. Pharmacol Biochem Behav 23: tive for delta-opioid receptors produced a small (2-fold), 731-736 but significant, reduction in the potency of cocaine to Herling S, Coales EH Jr, Valentino RJ, Hein DW, Woods JH (1980) discrimination in pigeons. J Pharmacol Exp produce its discriminative stimulus effects in rats (Su- Ther 214:139-146 zuki et al. 1994). Taken together, these studies suggest Jewett DC, Schaal DW, Cleary J, Thompson T, Levine AS (1991) delta-opioids can modulate the discriminative stimulus The discriminative stimulus properties of neuropeptide Y. effects of cocaine in rats. In the present study, however, Brain Res 561:165-168 we found no evidence for cocaine producing discrimina- Jewett DC, Cleary J, Schaal DW, Thompson T, Levine AS (1993) [Leu 31, Pro 34] Neuropeptide Y (NPY) , but not NPY 20-36, tive stimulus similar to those of DPDPE in pigeons. produces discriminative stimulus effects similar to NPY and In order to evaluate further the notion that delta-opio- induces food intake. Brain Res 631:129-132 id receptors mediate the discriminative stimulus effects Jiang Q, Mosberg HI, and Porreca F (1990) Antinociceptive ef- of DPDPE, studies were performed with naltrindole, an fects of [D-Ala2]deltorphin II, a highly selective delta agonist in vivo. Life Sci 47:PL43-PL47 antagonist selective for delta-opioid receptors. A small Karten HJ, Hodos W (1967) A stereotaxic atlas of the brain of the dose of naltrindole (0.1 mg/kg, IM) antagonized the dis- pigeon (Columba livia). Johns Hopkins Press, Baltimore criminative stimulus and rate decreasing effects of Koek W, Kleer E, Mndar PJ, Woods JH (1986) -like DPDPE by approximately 30-fold. Small doses of naltr- catalepsy induced by the excitatory amino acid antagonist DL- 2-amino-5-phosphonovalerate. Beh Brain Res 19:257-259 indole have previously been found to antagonize the dis- Mattia A, Vanderah T, Mosberg HI, Porreca F (1991) Lack of anti- criminative stimulus of BW373U86, but not those of the nociceptive cross-tolerance between [D-Pen2-D-PenS]enkepha- mu-opioid agonist morphine (Comer et al. 1993). Also, lin and [D-Ata2]deltorphin II in mice: evidence for delta recep- naltrindole was 32- to 100-fold more potent in antago- tor subtypes. J Pharmacol Exp Ther 258:583-587 nizing the discriminative stimulus and rate-decreasing Mosberg HI, Hurst R, Hruby VJ, Gee K, Yamamura HI, Galligan JJ, Burks TF (1983) Bis-penicillamine possess effects of DPDPE than reducing the potency of morphine highly improved specificity toward 5 opioid receptors. Proc to produce discriminative stimulus (Comer et al. 1993) Natl Acad Sci USA 80:5871-5874 230 Negus SS, Burke TF, Medzihradsky F, Woods JH (1993) Effects of Suzuki T, Mori T, Funada M, Misawa M, Nagase H (1994) Atten- opioid agonists selective for mu, kappa and delta opioid recep- uation of the discriminative stimulus properties of cocaine by tors on schedule-controlled responding in rhesus monkeys: an- delta-opioid receptor antagonists. Eur J Pharmacol 263: 207- tagonism by . J Pharmacol Exp Ther 267: 896- 211 903 Ukai M, Holtzman SG (1988) Morphine-like discriminative stimu- Picker MJ, Dykstra, LA (1987) Comparison of the discriminative lus effects of opioid peptides: Possible modulatory role of D- stimulus properties of U50,488 and morphine in pigeons. J Alaa, D-LeuS-enkephalin (DADL) and A (1-13). Pharmacol Exp Ther 243:938-945 Psychopharmacology 94:32-37 Shearman GT, Herz A (1982) D-Ala 2, D-LeuS-enkephalin general- Ukai M, Mori E, Kameyama T (1993) Cocaine-like discriminative izes to a discriminative stimulus produced by fentanyl but not stimulus properties of the delta-selective opioid receptor ago- ethylketocyclazocine. Pharmacol Biochem Behav 16: 249- nist, [D-Pen2-L-PenS]enkephalin in the rat. Eur J Pharmacol 252 231:143-144